7. Project Summary/Abstract This SBIR application is proposed in response to RFA-DA-19-019, the HEAL Initiative on building technologies to stop the opioid crisis. Creative Bio-Peptides, Inc. is committed to providing effective and safe non-opioid treatments for the 50 million Americans suffering daily pain and the 2 million who live with opioid dependency or addiction. Current decades-old addiction treatments like methadone are not up to the magnitude of this problem, and themselves have abuse liability concerns. Chemokines (hormones of the immune system that mediate innate immune inflammation) enhance pain, reduce opioid analgesia, and promote drug-seeking behavior and addiction ? giving them a central role at the crossroads of chronic pain and the opioid crisis. So, blocking chemokines (rather than opioid receptors) provides an exciting and untested treatment opportunity for pain and opioid use disorders (OUD). Our chemokine antagonist (blocker) peptide R103 stops neuropathic pain and enhances the potency of morphine to relieve acute pain. Recent studies suggest that R103 could also become an effective treatment for OUD. Other drugs, that block the same chemokine receptors targeted by R103, lower the rewarding and reinforcing effects of drugs of abuse. Using rat behavioral studies that model human drug-taking, we and others have reported that a CXCR4 antagonist AMD3100 (Plerixafor), a CCR5 antagonist Maraviroc (Selzentry), and a CCR2 antagonist reduce the rewarding and locomotor effects of drugs of abuse. However, the only two approved treatments each block only one receptor target and have significant safety concerns (need to be injected, allergic risks and/or liver toxicity). R103 is a preferred treatment, as it blocks multiple chemokine receptors (CCR2/CCR5/CXCR4), is more potent and our prior clinical analog (very similar peptide) had no safety issues in humans. We propose to assess, in animal self-administration models that mimic human drug-taking, whether R103 reduces morphine intake. Success will be defined as a >50% reduction in the breakpoint difference score, a measure of motivation for drug-taking. Physical dependence develops during chronic opioid exposure and upon discontinuation of opioid intake, presents as a withdrawal syndrome that triggers opioid relapse. We will further assess if R103 will prevent or blunt naloxone-precipitated withdrawal signs in morphine-dependent rats and stop relapse. Success will be a >50% reduction in the ?Withdrawal Symptom Score? of R103 compared to vehicle. We will also evaluate the safety of R103 by determining a maximum tolerated dose. Successful execution of this program will create new intellectual property, de-risk IND-enabling studies of R103 in Phase II development, and will culminate with a pre-IND meeting with the FDA to establish a regulatory approval plan for our subsequent human efficacy studies in OUD. Creative Bio-Peptides, Inc has obtained two issued patents for R103, the composition of matter (US10,071,153) and the use in treating neuropathic pain (US10,130,674). We have ten pending applications, including uses of R103 to reduce morphine use in pain, and as a treatment for addictions.